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Mental Health and Ketamine: Part III

~ This blog series is about my approach to mental health and the integration of ketamine therapy with a psychodynamic and affective neuroscientific lens ~

How Does Ketamine Work?

While this list is not exhaustive, it should give a decent overview on the various mechanisms through which ketamine may positively effect mental health. This final blog will be more technical than the previous two simply due to the complexity of the concepts.

NMDA Receptors

There are plenty of working theories, most, if not all of them are mechanistic and neuroanatomical in nature. Such theories start with the NMDA glutamate receptor subtype, where ketamine acts as a strong inhibitor. Since glutamate is the brain’s primary excitatory neurotransmitter, its inhibition at the NMDA receptors results in a broad span of effects. Consequently, this NMDA inhibition mechanism has to be constrained to a high-resolution brain region where NMDA-positive neuron populations are known. This is because NMDA-positive neurons do not intrinsically connect downstream to excitatory processes. For example, a glutamate-signaling neuron, 'A', may be responsible for inhibiting/stopping the transmission it received by its upstream neuron as it makes a synapse with, 'B', as neuron B could be excitatory or inhibitory. To complicate matters further, there may be hundreds of collateral inputs to neuron B that influence the action of neuron A. So, the NMDA receptor inhibition is an accurate observation and is true, but only applies at a very resolute level of analysis, say when looking at neuronal populations in the nucleus accumbens or lateral habenula.

AMPA Receptors

The next cell signaling mechanism is through another family of glutamate receptors called AMPA receptors. AMPA receptors are kind of like a gateway to a venue that only allows special types of guests to enter, but once enough of them do then the venue is open to the more common-place guests that can enter through the NMDA gates. AMPA receptors are needed for the development of learning, association, and contextualization that is ultimately maintained by NMDA receptor activity. This is the basis for neuroplasticity, along with the growth signals that come from molecules like brain-derived neurotrophic factor and post-synaptic density protein-95. Ketamine, through intracellular signaling cascades, increases glutamate signaling and AMPA receptor density across the brain, but particularly in the nucleus accumbens, hippocampus, prefrontal cortex, and other subcortical midline structures. Consequently, with increased AMPA density and reduced NMDA activation, circuits that have been hyper-plasticized may undergo structural changes that reflect a more un-learned state, especially if certain brain functions are being exercised at the same time. The importance of this ‘un-learning’ will be highlighted in the next section.

Aleksandrova, L. R., Wang, Y. T., & Phillips, A. G. (2017). Hydroxynorketamine: Implications for the NMDA Receptor Hypothesis of Ketamine's Antidepressant Action. Chronic stress (Thousand Oaks, Calif.), 1, 2470547017743511. https://doi.org/10.1177/2470547017743511

Chronic Stress Reversal

As highlighted in the previous blogs, chronic stress, repeated social defeat, and loss of status can fertilize mental health fragility through the intrinsic affective systems that generate psychic pain. Experience with these negative events coupled with potentially already increased susceptibility (from childhood attachment insecurity) begins to be ‘written in stone’, so-to-speak. In this case, neuroplasticity is not in the favor of the higher self, but instead encodes lower hierarchical status, increased negative self-reflection, and negative affect. For some, the resilient folks, such negative affect evokes a rebound sense of potential redemption and hope because, well, they probably screwed up - but at least it’s their fault and they can attempt to fix themselves so the circumstance isn’t likely to happen again. Others may fall into the role of the victim, searching outside of themselves for the answer to why they were rejected. Whichever it is, the point here is that if stress happens and it is not sufficiently explored and understood, then it is likely to continue to eat away at the ability to self-regulate emotional tone. Chronic social defeat stress has been documented to cause negative structural and functional changes in many different brain areas. Some areas include the prefrontal cortices, cingulate cortices, hippocampi, and deeper limbic structures like the nucleus accumbens, lateral habenula, and ventral tegmental area. Such changes are associated with functional deficits in socialization, immune strength, emotional resiliency, motivation, and self-perception. So, what if we could reverse the neurostructural changes that mediate the plastic response to chronic social defeat stress and loss? Well, it appears that through the aforementioned glutamatergic and cell signaling mechanisms, ketamine does act in such a way.

Neuronal Network Shifts

The brain consists of many large-scale networks, but there are three primary ones that interface between the subconscious and conscious levels: the default mode network (DMN), the salience network (SN), and the frontoparietal network (FPN). DMN disruption has been shown to be a classical mediator of mystical experience and ‘ego-dissolution’ in psychedelic literature. The DMN operates on unconscious memory, which is largely unavailable to conscious consideration. It manifests in behaviors, attitudes, and feelings as well as in much more complex forms such as defenses, self-esteem, and transference. Major depressive disorder (MDD) is hypothesized to be associated with dysfunction in large-scale brain networks, especially hyper-connectivity within the DMN. Abnormally increased resting-state functional connectivity within the DMN has been associated with dysfunctional self-referential processing, rumination, and severity of depression. Therefore, abnormal functional connectivity has been indicated as a trait biomarker of depression and a potential therapeutic target. This observation is important in affect regulation because of the interruption of negatively-biased unconscious narrative that arises from the neurotic right orbitomedial/ventromedial prefrontal cortex (om/vmPFC). This interruption allows the hyper-critical superego, developed from cultural and familial expectation, to undergo assimilation of unconscious dreams, desires, and complexes, or at least the chance to shed unfair perseverative self-judgments. Such unconscious dreams are the birthplace of thought, clarifying them may progress to conscious manipulation of thought patterns, which are then more likely to lead to action and behavior change that is more in line with who the individual desires to be. There are also changes in some of the salience network nodes that are responsible for determining what in the environment is worth paying attention to. In MDD, for example, heightened sensitivity to body signals leads to increased self-referential processing, reduced pain threshold, and reduced processing ability of external stimuli. All of these networks simplify our personal experiences by running the software that has been written in early life. They designate what we should pay attention to, what we should value, explore, avoid, exploit, etc., without which we would be paralyzed with indecision. Ketamine’s disruption of some of these nodes seems to allow new patterns of thought and mental exploration to take place without the intense vulnerability and negative emotion that accompanies a change in very deep-rooted software – especially with the guidance of a therapeutic aim.

Back to Affective Neuroscience

To tie it all together I will return to an affective neuroscience perspective, which I believe to be the fundamental piece of the structure that all of these other mechanisms are built on top of. From the primal affective perspective, ketamine seems to result in increased activation of SEEKING as well as PLAY. This idea is supported by literature that shows ketamine-dependent increases in dopamine levels in the brain, a neurotransmitter at the core of the SEEKING system. Additionally, co-administration of dopamine receptor antagonists block some of ketamine’s anti-depressant effects, further reinforcing the necessity of SEEKING activation in alleviating negative emotion. It is important to distinguish the incentive and consummatory rewards that are mediated by dopamine, as the consummatory reward is not associated with ketamine’s action. The activation of the SEEKING system is associated with goal-directed behavior and is the affective source of pursuit euphoria, a very different phenomenological experience than consummatory reward. It is the motivational force that designates the importance of such a pursuit. Anhedonia is a phenomenological state where SEEKING is blunted and motivation to pursue previously pleasurable activities is absent. This condition is greatly softened with intravenous ketamine. On the other hand, there are consequences of pathological SEEKING, as has been demonstrated in conditions of mania, delusions of grandeur, and even hyper-religiosity, where administration of dopamine receptor inhibitors (anti-psychotics) rather than activators is the normal therapeutic course. Indeed, administration of ketamine to schizophrenics worsens positive symptoms, but it is important to note that ketamine is still used in psychotic disorders where negative symptoms of anhedonia, depression, and suicidality are primary. It is also plausible that the increase in SEEKING behavior could be a secondary benefit to the reduction in negative emotion, as ketamine seems to reduce FEAR, RAGE, and PANIC through opioidergic signaling (the opioid antagonist naltrexone blocks some anti-depressant effects), direct glutamatergic inhibition in the PANIC system, and a reduction in dynorphin signaling. Altogether, the improvements following intravenous ketamine therapy seem to characterize an improvement in the positive affective systems SEEKING and perhaps PLAY, while reducing negative affective systems FEAR, RAGE, and PANIC. It isn’t clear if positive affect enhancement or negative affect softening happens first, or if they happen together. Either way, the result is a reduction in psychic burden along with the return of a glimmer of hope in the form of motivation and clearer understanding.


The goal of this blog series was to invite people into my process of what ketamine-assisted psychotherapy looks like in theory and in practice. There are many moving pieces when viewed through a complex systems approach – I didn’t even touch on other physiological contributors to mental health status, such as nutrition, microbiome composition, inflammation, hormonal dysfunction, medication use, etc. Perhaps in a future blog.

Integrating and connecting the working theories and hypotheses about the mechanisms of ketamine will no doubt give rise to a more rigorous approach to its use and study. The clinical effects of ketamine can be described on many different levels of analysis, from the purely neurochemical to psychodynamic reorganization. As a provider of ketamine, it is important to understand, to the extent that one can, the application of ketamine to each of the levels of analysis. If congruity can be established across multiple theories and models, a greater, arch-theory may be founded. Furthermore, not every individual presents on the same level of analysis in regard to neuropsychological health. So, having alternative explanations for the pleiotropic effects of ketamine may help expand the inclusion criteria based on different theoretical approaches, i.e depression vs. anhedonia vs. cognitive decline.

I hope this series has been helpful, and if you feel that you could benefit from this approach please reach out and let us know!

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